Blood coagulation is the first line of defense against blood loss following injury. The blood coagulation “cascade” involves a number of circulating serine protease zymogens, regulatory cofactors and inhibitors, as shown in FIG. 1. Each enzyme, once generated from its zymogen, specifically cleaves the next zymogen in the cascade to produce an active protease. This process is repeated until finally thrombin cleaves the fibrinopeptides from fibrinogen to produce fibrin that polymerizes to form a blood clot. Although efficient clotting limits the loss of blood at a site of trauma, it also poses the risk of systemic coagulation resulting in massive thrombosis. Under normal circumstances, hemostasis maintains a balance between clot formation (coagulation) and clot dissolution (fibrinolysis). However, in certain disease states such as acute myocardial infarction and unstable angina, the rupture of an established atherosclerotic plaque results in abnormal thrombus formation in the coronary arterial vasculature.
Despite the availability of a number of approved anticoagulant therapies, myocardial infarction, unstable angina, atrial fibrillation, stroke, pulmonary embolism, and deep vein thrombosis represent areas of major medical need. Cardiovascular diseases (e.g., acute myocardial infarction, stroke, and pulmonary embolism) disable or kill more people in the developed world than any other disease. Over two million patients are hospitalized each year in the U.S. for acute arterial thrombosis and stroke. The worldwide population for acute arterial antithrombotic therapy is five to six million, while over 25 million patients have chronic arterial thrombosis. Over 10 million individuals are candidates for venous thrombosis therapy.
A large medical need exists for novel anticoagulation drugs that lack some or all of the side effects of currently available drugs, such as the risk of bleeding episodes and patient-to-patient variability that results in the need for close monitoring and titration of therapeutic doses. Current anticoagulant therapies that dominate the market include injectable unfractionated and low molecular weight (LMW) heparin, and orally administered warfarin (coumadin).
Three phases of the coagulation cascade can be described, namely initiation, amplification, and propagation (see FIG. 1). Inhibiting enzymes of the propagation phase, i.e., Factor Xa and Factor IIa (thrombin), has been an area of active interest in the pharmaceutical industry for some time. The first generation of thrombin inhibitors to reach the clinic were polypeptides derived from natural sources, such as the potent anticoagulant, hirudin, which is a leech peptide. Potent, orally available, small molecule thrombin inhibitors have been discovered over the past few decades. Some of these are now in the clinic or are ready to be marketed. Efforts to develop potent Factor Xa inhibitors are not far behind. Targeting enzymes involved in propagation (e.g., hirudin) does not appear to be ideal since inhibitors of this phase of the coagulation cascade are associated with severe bleeding. This is further supported by findings that Factor V and Factor X deficiencies are associated with severe bleeding episodes.
Several new treatments under development are aimed at the initiation phase that involves Factor VII and tissue factor (TF). These include an active site-blocked Factor VIIa, a high affinity neutralizing antibody against TF, and a nematode protein (NAPcc) that inhibits Factor VIIa/TF. Because these approaches target the very start of the coagulation cascade, they may lead to bleeding episodes.
Due to the limited efficacy and adverse side-effects of some current therapeutics for the inhibition of undesirable thrombosis (e.g., deep vein thrombosis and stroke), improved compounds and methods are needed for preventing or treating undesirable thrombosis.